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Crosstalk between transcription factors responsive to LPS and anti-inflammatory agents

对 LPS 和抗炎药物敏感的转录因子之间的串扰

基本信息

批准号：
13671957
负责人：
OHURA Kiyoshi
金额：
$ 1.92万
依托单位：
Osaka Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13671957/
关键词：
PPARγ macrophages natural immunity inflammation nuclear transcription factor prostaglandins

项目摘要

15-Deoxy-Δ^<12,14>-prostaglandin J_2 (dPGJ_2) is a metabolite of prostaglandin D_2, that binds to peroxisome proliferator-activated receptor γ (PPARγ). PPARγ and prostaglandin D_2 synthase, which is required for dPGJ_2 synthesis, are predominantly expressed in macrophages. In contrast, IL-10 and IL-12 produced by macrophages stimulate Th1 and Th2 immune response, respectively. This study investigated the effect of dPGJ_2 on IL-10 and IL-12 production by macrophages in response to lipopolysaccharide (LPS). Our data clearly demonstrated that dPGJ_2 inhibits LPS-induced IL-10 and IL-12 production by macrophages. A different agonist of PPARγ, *3-hydroxyoctadecadienoic acid, similarly inhibited the production of IL-10 and IL-12 in response to LPS. Further, dPGJ_2 did not appear to act through the PGD_2 receptor. These results suggest that dPGJ_2 may inhibit LPS-induced IL-10 and IL-12 production by macrophages through PPARγ. Prostaglandin D_2 (PGD_2) acts via the adenyl cyclase-coupled receptor for PGD_2 (DP receptor). Here we present evidence that BW245C, a DP receptor agonist, modulates macrophage functions related to natural immunity. BW245C inhibited macrophage chemotaxis at concentrations of 0.1 to 10 μM and phagocytosis of Escherichia coli by macrophages at a concentration of 10 μM. In addition, BW245C inhibited the production of superoxide anion by PMA-stimulated macrophages at concentrations of 0.1 to 10 μM and nitrite production by LPS-stimulated macrophages at a concentration of 10 μM. In contrast, BW245C potentiated the production of TNF-α, a pro-inflammatory cytokine, by LPS-stimulated macrophages at concentrations of 1 to 10 μM. These results suggest that PGD_2 may modulate macrophage functions related to natural immunity via DP receptor.

15-脱氧-Δ^<12，14>-前列腺素J_2（dPGJ_2）是前列腺素D_2的代谢产物，与过氧化物酶体增殖物激活受体γ（PPARγ）结合。过氧化物酶体增殖物激活受体γ（PPARγ）和前列腺素D_2合成酶（PGED_2 synthase）主要在巨噬细胞中表达。相反，由巨噬细胞产生的IL-10和IL-12分别刺激Th 1和Th 2免疫应答。本研究观察了dPGJ_2对脂多糖（LPS）诱导的巨噬细胞产生IL-10和IL-12的影响。我们的数据清楚地表明，dPGJ_2抑制LPS诱导的巨噬细胞产生IL-10和IL-12。一种不同的PPARγ激动剂，*3-羟基十八碳二烯酸，类似地抑制了响应于LPS的IL-10和IL-12的产生。此外，dPGJ_2似乎不通过PGD_2受体起作用。上述结果提示dPGJ_2可能通过PPARγ抑制LPS诱导的巨噬细胞产生IL-10和IL-12。前列腺素D_2（PGD_2）通过其腺苷酸环化酶偶联受体（DP受体）发挥作用。在这里，我们提出的证据表明，BW 245 C，DP受体激动剂，调节与自然免疫相关的巨噬细胞功能。BW 245 C在0.1至10 μ M浓度下抑制巨噬细胞趋化性，在10 μM浓度下抑制巨噬细胞对大肠杆菌的吞噬作用。此外，BW 245 C在0.1至10 μ M浓度下抑制PMA刺激的巨噬细胞产生超氧阴离子，在10 μM浓度下抑制LPS刺激的巨噬细胞产生亚硝酸盐。相比之下，BW 245 C在1至10 μM的浓度下增强LPS刺激的巨噬细胞产生TNF-α（一种促炎细胞因子）。提示PGD_2可能通过DP受体调节巨噬细胞与天然免疫有关的功能。